Debunking myths on genetics and DNA

Sunday, August 17, 2014

A mosaic vaccine that could potentially protect from different ebola strains

Disclaimer: The mosaic vaccine paper discussed in this article is from my own group and overlaps with some of the research I do.

I'm sure you've been following the latest news about the Ebola virus outbreak in Africa.

"The Ebola outbreak in West Africa is the world's deadliest to date and the World Health Organization has declared an international health emergency as more than 1,000 people have died of the virus in Guinea, Liberia, Sierra Leone and Nigeria this year." [Source: BBC News]

The ebola virus was first described in 1976, with outbreaks reported starting from 1967 [3]. It's part of the Filovirus family and its natural reservoir is believed to be fruit bats, though there is evidence that it could be wider than we think. In fact, ebola can infect other animals like monkeys and pigs. Because the virus is transmitted through bodily fluids and it can survive for a few days after the host's death, it can be easily spread through the butchering and consumption of bushmeat.

You've probably heard from the news that two infected Americans were treated with "serum". Some headlines even dubbed it a "secret serum." The serum is actually no secret and has been used not just for ebola but also for other viruses like RSV [1]. The treatment, called passive transfer of antibodies (or antibody serum), is based on the transfer of antibody serum from one organism to another. The idea behind it is that the immune system of a person previously exposed to the virus has developed antibodies that can help other immunologically naive patients fight the infection. For the ebola virus, the therapy is still in the experimental phase and, up to these two patients, had only been tested in animals.

There are several vaccines currently being tested, each one at various experimental phases. Friedrich et al. [1] list a nice summary of all the current testing in their review. The one they do not mention in their review is a mosaic vaccine being developed by my group, which is based on ideas originally designed for an HIV vaccine.

What is a mosaic vaccine?

A vaccine is an attenuated form of a virus. Even though unable to start a full infection, when injected into the body, the attenuated virus is detected by the immune system, which can then mount the appropriate response and "create" neutralizing antibodies. Typically, the attenuated virus is created from the natural virus found in organisms.

And then came HIV and baffled everyone.

The problem with HIV is that every single HIV-infected person has a different virus. In order to protect from every possible infection, one would need to put into a vaccine the over half a million genetically distinct circulating strains. Clearly, that's not possible. How do you protect people from a viral population that's so diverse? Natural strains are no longer sufficient. You have to come up with clever ways to 'summarize' the whole population of viruses with just 2-3 viral strains.

That's when computers come in handy: the mosaic vaccine is a vaccine created in silico. Suppose you want to create one genetic sequence that "summarizes" all the genetic variants found in a population of 100 strains. The algorithm that creates the mosaic starts from the 100 strains and it literally reshuffles them bit by bit. The "bits" are not cut out randomly but in a way that, when reassembled in a full genome, the proteins are still functional and working. In other words, you want to make sure that after the reshuffling you still have functioning viruses. You repeat the reshuffling for a few times and at the end of the iterations you pick the one strain that best represents the original pool of 100 genomes.

HIV-1 mosaic vaccines have given great results in guinea pigs and monkeys. But what would be the advantage of using them for ebola?

If you are familiar with phylogenetics, you will certainly object that the two viruses (HIV and ebola) are quite different: while HIV spreads out in a star-like fashion (which translates into the fact that no two individuals have the same virus), ebola evolves more like the flu, with new emerging viruses causing new outbreaks. So, why would the mosaic vaccine help with ebola?

"While the techniques used here are very similar to those used for HIV-1 mosaic vaccine design, a pattern of repeated introductions of the filoviruses into humans (and primates generally) gives a crucial difference from HIV-1. HIV-1 shows great diversity within the pandemic, but that diversity has developed continuously, leaving intermediate isolates in its wake. In contrast, known filovirus diversity has episodically increased as new outbreaks are found to result from novel viruses, lacking intermediates." [3]

The fact that the ebola virus "lacks intermediates" seems to indicate that there are reservoirs that we don't know of where the virus accumulates diversity. This is worrisome: we not only need to protect from the current outbreaks, but also be prepared for new viruses that might emerge in the future. In [3], Fenimore et al show how the mosaic algorithm can be readapted from HIV to ebola, accounting for the evolutionary differences between the two viruses.

A mosaic vaccine would protect from all ebola subspecies and also against new strains that could potentially develop from the current outbreaks. The problem with ebola is that its reservoir could be wider than we think. The viral diversity found in bats has not matched the diversity of the ebola strains found in humans. So, where are the new viruses coming from? There are likely pockets of diversity that come from reservoirs we don't know of.

"The implication is that a vaccine against the filoviruses should strive for good coverage of common epitopes from the maximum number of types and strains currently available, in the hope that future outbreaks will retain these elements, so the vaccine will still be effective when challenged by a novel strain in a new outbreak." [3]

The authors tested the ebola mosaic vaccine on a mouse model and compared it with a vaccine created with a single natural strain from Zaire. All vaccinated mice in either group (mosaic or natural) survived the challenge. The natural strain vaccine provided 82.8% coverage of other Zaire strains, but only 14.0% coverage of non-Zaire strains. On the other hand, the single mosaic vaccine provided 54.7% coverage of other Zaire strains (still sufficient to protect the mice from infection) and 23.2% coverage of non-Zaire ebola virus strains, proving that a mosaic can indeed improve protection against different subtypes. Furthermore, comparing a cocktail of a two-mosaic vaccine with a two-protein natural cocktail and a vaccine that was previously tested in macaques (Hensley et al., 2010), the mosaic cocktail achieved the highest coverage.

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ABOUT E.E. GIORGI

Award-winning author, photographer, computational biologist, hiker, and jazz lover. I blog about my greatest passions in life: books, photography and genetics. Some of the books I talk about are mine. All my writing and photographs are under a creative commons license. Commercial use is strictly forbidden without my permission.
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